N-palmitoylethanolamide for use in combination with a non-steroidal Anti-inflammatory drug in the treatment of inflammatory pain

Abstract

To provide combination administration for reducing the effective administration amount of nonsteroidal anti-inflammatory drug (NSAID).SOLUTION: Disclosed is palmitoylethanolamide for use in the treatment of inflammatory pain, in particular non-neuropathic inflammatory pain, where the palmitoylethanolamide is administered as needed in association or combination with a NSAID, where the administration is separate, combined, or simultaneous.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the use of N-palmitoylethanolamide (also known as palmitoylethanolamide or PEA) in combination with a nonsteroidal anti-inflammatory drug in the treatment of inflammatory pain. [Background technology]

[0002] Pain is one of the most common human health problems. Furthermore, in recent years, there has been increased attention paid to the recognition and management of pain in pets, especially cats and dogs. In fact, based on the latest definition of pain published by the International Association for the Study of Pain (IASP), to experience pain, it is not necessary to know how to express it in words, and even non-verbal subjects (such as animals) are fully included among organisms that can experience pain.

[0003] Pain is classified as acute, persistent, or chronic based on duration; and defined as nociceptive, inflammatory, or neuropathic based on cause. In conditions of tissue injury, inflammation causes the production and release of mediators that contribute to the enhancement of pain; in this case, the pain is defined as inflammatory.

[0004] Arachidonic acid derivatives play an important role among these mediators: in fact, prostaglandins, prostacyclins, and thromboxanes (prostanoids) produced by the action of the enzymes cyclooxygenase (COX)-1 (constitutive isoform) and COX-2 (inducible isoform) are involved in the hyperexcitation of nociceptors, leading to the manifestation of allodynia.

[0005] Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the treatment of inflammatory pain due to their inhibitory mechanism against COX. Diclofenac and meloxicam are two of the most common NSAIDs used in the treatment of inflammatory pain in both human and veterinary settings.

[0006] Diclofenac, an acetic acid derivative, is used to treat inflammatory and degenerative rheumatic conditions, diseases characterized by pain and inflammation in periarticular tissues such as tendons and ligaments, painful post-traumatic conditions, and menstrual pain. It is available in several formulations (e.g., oral, parenteral, rectal) and in various dosages, depending on the therapeutic indication and the severity of the symptoms. In all cases, it is recommended to use the product not more than 150 mg per day for a limited period of time.

[0007] Meloxicam has a relatively selective action on COX-2 and belongs to a subgroup of NSAIDs called "non-coxib COX-2 selective NSAIDs." It is used for the short-term treatment of exacerbations of osteoarthritis and for the long-term treatment of pain associated with rheumatoid arthritis and ankylosing spondylitis. It is available commercially in various pharmaceutical formulations, and the recommended daily dose is not to exceed 15 mg. It is also widely used in veterinary medicine, especially in the treatment of arthritis and postoperative pain in cats and dogs.

[0008] NSAIDs are widely used to manage inflammation and pain, but they cause serious side effects and are a cause for concern even today (Samal et al., J Maxillofac Oral Surg. 2021 Mar;20(1):63-69; Ringsten et al., Cochrane Database Syst Rev. 2023 Dec 11;12(12):CD015087; Bindu et al., Biochem Pharmacol. 2020 Oct;180:114147; Lascelles et al., Vet Ther. 2005 Fall;6(3):237-51; Wernham et al., Aust Vet J. 2023 Mar;101(3):90-98). Indeed, inhibition of prostaglandin production leads to the occurrence of dose-dependent adverse events involving kidney and liver toxicity, cardiovascular events, hypertension and gastrointestinal complications, especially in frail patients, e.g., elderly, renal patients or those receiving multiple treatments.

[0009] Therefore, there is a felt need for effective and safe treatments for the precise management of both acute and chronic inflammatory pain. To this end, it would be desirable to be able to reduce the effective dose of NSAIDs.

[0010] N-palmitoylethanolamide (or simply palmitoylethanolamide or PEA) is a palmitic acid amide commonly found in animal tissues and produced as needed under conditions of injury. It is known to have anti-inflammatory and anti-analgesic properties. Preclinical and clinical studies have demonstrated the effectiveness of administration of PEA, particularly in its micronized form (particle size 0.2-10 μm), in various types of inflammation and pain.

[0011] Its analgesic effects have also been compared with those of NSAIDs, more specifically ibuprofen and celecoxib, in patients with temporomandibular pain and chronic pelvic pain. Furthermore, one study demonstrated the efficacy of a two-week continuous administration of PEA in combination with celecoxib for temporomandibular pain, but did not compare it with the effects of single treatments. It should be noted that PEA has an excellent safety profile, lacking acute and subchronic toxicity up to at least 1000 mg / kg per day when administered in ultrafinely divided form (Nestmann Food Sci Nutr. 2016 Jun 15;5(2):292-309).

[0012] The combination of PEA with paracetamol, a non-NSAID antipyretic and analgesic that acts primarily via central mechanisms, has been studied and has demonstrated its benefits under conditions of both experimentally induced and spontaneous neuropathic pain, possibly due to the potent anti-inflammatory effects of PEA, especially in its ultrafinely divided form, also at the level of the central nervous system.

[0013] However, it is important to emphasize that the therapeutic improvement of combining different analgesics is not clear, as shown by the association between NSAIDs and paracetamol with no additional benefit.

[0014] Continuous, long-term prophylactic use (3 months) of ultrafine-grained PEA in combination with one or more NSAIDs (ibuprofen, diclofenac, or nimesulide) as needed was advantageous over the as-needed use of NSAIDs alone in patients with headache with and without aura. This benefit arose from 2 or 3 months of treatment with PEA and affected patients with migraine, a "syndrome" considered to be associated with central changes typical of neuropathic pain. However, the existence of a synergistic interaction between PEA and NSAIDs has not been demonstrated.

[0015] In conclusion, the prior art does not describe or suggest as-needed treatment with PEA in combination with an NSAID, especially in non-neuropathic inflammatory pain conditions. Summary of the Invention

[0016] The present invention originates from the surprising finding that palmitoylethanolamide (PEA), preferably used in ultrafine form, when administered in combination with nonsteroidal anti-inflammatory drugs, shows synergistically related effects in the treatment of inflammatory pain, especially non-neuropathic inflammatory pain, and benefits patient safety in terms of reducing the incidence and severity of the dose-dependent side effects typical of these drugs.In particular, the synergistic effect between PEA and NSAIDs in the treatment of inflammatory pain in humans and animals can enhance the anti-inflammatory effect of NSAIDs and reduce their active dose.

[0017] The present invention therefore relates to palmitoylethanolamide for use in the treatment of inflammatory pain, particularly non-neuropathic inflammatory pain, wherein the palmitoylethanolamide is optionally administered together or in combination with a non-steroidal anti-inflammatory drug, said administration being separate, combined or simultaneous.

[0018] The present invention further relates to compositions comprising palmitoylethanolamide and a nonsteroidal anti-inflammatory drug, particularly compositions that can be used to treat inflammatory pain.

[0019] These and further objects, as outlined in the appended claims, are set forth in the following description, the text of which should be considered included in the description to assess the sufficiency of the description.

[0020] Further characteristics and advantages of the invention will become apparent from the following description of preferred embodiments given by way of non-limiting indication. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 shows inflammatory pain tolerance thresholds measured by paw pressure testing in response to various treatment groups as indicated in the legend. [Figure 2] FIG. 2 shows a comparison between the mean values±SEM of the AUC obtained starting from the data shown in FIG. [Figure 3] FIG. 3 shows inflammatory pain tolerance thresholds measured by paw pressure testing in response to various treatment groups as indicated in the legend. [Figure 4] FIG. 4 shows a comparison between the mean values±SEM of the AUC obtained starting from the data shown in FIG. [Figure 5] FIG. 5 shows a particle size distribution curve of ultra-micronized PEA according to an embodiment, obtained by the laser scattering method described below. [Figure 6] Figure 6 shows the effect of treatment on arthritis severity starting from the first day of treatment (day 25) to the end of the study. Scores are expressed as mean ± SEM. *p<0.05 and **p<0.0001 vs. vehicle; #p<0.0001 vs. IBUld; §p<0.05 and §§p<0.0001 vs. PEA. [Figure 7]Figure 7 shows the effect of treatment on paw swelling. Paw volume increase is expressed as mean ± SEM. *p<0.05 and **p<0.0001 vs. vehicle; #p<0.0001 vs. IBUld; §p<0.05 and §§p<0.0001 vs. PEA. [Figure 8] Figure 8 shows the effect of treatment on arthritis pain-induced weight loss. The arrow indicates the start of treatment. Values ​​are expressed as mean ± SEM. *p<0.05 and **p<0.0001 vs. vehicle; #p<0.0001 vs. IBUld; §p<0.05 and §§p<0.0001 vs. PEA. [Figure 9] Figure 9 shows the analgesic effect of treatment. The effect was measured using Von Frey filaments and is expressed as pain tolerance threshold in grams. *p<0.05 vs. veh; #p<0.05 vs. IBU-ld; §p<0.05 vs. PEA. [Figure 10] Figure 10 shows the effect of chronic treatment (14 days) with test substances used individually or in combination on nociceptive thresholds measured by the paw pressure test. The significant decrease in threshold induced by CFA is effectively counteracted by all treatments tested. *p<0.05 and **p<0.0001 for veh; #p<0.05 and ##p<0.0001 for ctrl; §p<0.05 and §§p<0.0001 for Decl. DETAILED DESCRIPTION OF THE INVENTION

[0022] In a first aspect, the present invention relates to palmitoylethanolamide for use in the treatment of inflammatory pain, particularly non-neuropathic inflammatory pain, wherein the palmitoylethanolamide is optionally administered together or in combination with a non-steroidal anti-inflammatory drug, said administration being separate, combined or simultaneous.

[0023] The terms "together" or "in combination" refer to both combination treatments and treatments in which PEA and a nonsteroidal anti-inflammatory drug (hereinafter referred to as an NSAID) are contained in a single dosage form.

[0024] The term "as needed" refers to administration, also known as "on demand," and can include a single dose or multiple doses, including single or multiple doses within a time interval of one day to one week, and includes administration of PEA and NSAIDs after the onset of non-neuropathic inflammatory pain. Such terms should be understood to exclude continuous preventive, prophylactic, or therapeutic administration.

[0025] The term "continuous administration" refers to the administration of several doses of a drug over a period of more than one week, more typically over a period of more than one month.

[0026] "Separate" administration means administration of the PEA and NSAID at different times ranging from one minute to several hours apart, for example 8, 12 or 14 hours apart.

[0027] "Combined" administration refers to administration of the PEA and NSAID contained in a single dosage form, ie, pharmaceutical or veterinary composition or formulation.

[0028] "Concurrent" administration means that the PEA and NSAID are administered in separate dosage forms but at the same time, i.e., within a separation time of not more than one minute between administration of the PEA and NSAID, or vice versa.

[0029] Palmitoylethanolamide can be administered in any form, for example, non-micronized, micronized or ultra-micronized.

[0030] The term "non-micronized palmitoylethanolamide (or PEA)" means a PEA having a particle size distribution, defined as a volume percentage, measured by laser light scattering and represented by a distribution curve with a mode greater than 10 μm, preferably greater than 20 μm.

[0031] The term "micronized palmitoylethanolamide (or PEA)" refers to a PEA having a particle size distribution, defined as a volume percentage, measured by laser light scattering and represented by a distribution curve having a mode between 6 μm and 10 μm.

[0032] The term "ultramicronized form of palmitoylethanolamide (or PEA)" means a PEA having a particle size distribution, defined as a volume percentage, measured by laser light scattering and represented by a distribution curve with a mode below 6 μm and above 0.5 μm.

[0033] Preferably, the PEA is in ultra-micronized form.

[0034] In one embodiment, the ultra-micronized form of PEA has a particle distribution as defined above and measured on a Malvern Mastersizer 3000 instrument using the Fraunhofer calculation algorithm, and in which at least 90% by volume, more preferably at least 95% by volume, of the particles have a particle size of less than 6 μm (d90=6 μm).

[0035] In a particularly preferred embodiment, the ultra-micronized form of PEA has a particle size distribution as defined above and measured on a Malvern Mastersizer 3000 instrument using the Fraunhofer calculation algorithm, and having a mode of 2-4 μm, with 100% by volume of the particles being less than 10 μm and at least 60% by volume of the particles being less than 3 μm.

[0036] As defined in the European Pharmacopoeia (section 2.9.31), particle size measurements performed by laser light diffraction and expressed as d90 (the maximum size of 90% by volume of the particles present in a sample) must be considered to have a variability of ±15% for d90 values ​​above 10 μm and ±30% for d90 values ​​below 10 μm. This means that a d90 of 6 μm measured by this method is actually understood to fall within the range of 4.2 to 7.8 μm. In other words, as an example, a d90 of 7 μm measured by laser light diffraction on a sample falls within the definition of d90 = 6 μm as defined in this patent application.

[0037] The micronization may be carried out in a fluid jet system (e.g., a Jetmill® model system) that operates on a spiral technique using compressed air or nitrogen jets that can utilize kinetic energy instead of mechanical energy to break up particles. Such equipment is conventional and will therefore not be described further except as related to the following features: The inner diameter of the atomization chamber is approximately 300 mm; Fluid jet pressure 10-12 bar; Product supply rate: 9~12kg / hour.

[0038] The present invention further relates to a composition comprising palmitoylethanolamide and an NSAID. Preferably, the composition of the present invention consists of a dry mixture of palmitoylethanolamide / NSAID. More preferably, the palmitoylethanolamide is in micronized (m-PEA) or ultra-micronized (um-PEA) form, and even more preferably, the palmitoylethanolamide is um-PEA or a mixture of at least two selected from um-PEA, m-PEA, and / or non-micronized PEA.

[0039] The NSAID is preferably Salicylates, e.g. acetylsalicylic acid Acetic acid derivatives, such as indomethacin, diclofenac, ketorolac, and aceclofenac Propionic acid derivatives, such as ibuprofen, ketoprofen and naproxen Oxicam derivatives, such as piroxicam and meloxicam Fenamates, e.g. mefenamic acid Coxibs or COX-2 inhibitors, such as cerocoxib, etoricoxib, and parecoxib Nimesulide Morniflumate / niflumic acid is selected from.

[0040] Preferably, the NSAID is selected from diclofenac, meloxicam, ibuprofen and ketoprofen.

[0041] Whether administered separately or combined in a single formulation, the PEA and NSAID are administered in a PEA / NSAID weight ratio of 20:1 to 1:1, preferably 12:1 to 5:1. More specifically, when the PEA is in ultra-micronized form, the PEA / NSAID weight ratio is 11:1 to 3:1, more preferably 10:1 to 5:1. When the PEA is in micronized or non-micronized form, the PEA / NSAID weight ratio is 20:1 to 5:1, more preferably 18:1 to 10:1.

[0042] Based on such weight ratios, which demonstrate significant synergistic effects, the minimum daily dose of PEA in both the combined treatment and the PEA / NSAID composition is at least 2.5 mg / day to 120 mg / day. Preferably, when um-PEA is used, the minimum daily dose of um-PEA is 4 mg / day to 66 mg / day, while when non-micronized PEA or m-PEA is used, the minimum daily dose is 5 mg / day to 120 mg / day.

[0043] Such dosages may vary depending on the subject, particularly if the subject is a child, an adult, or an elderly person.

[0044] Given the low toxicity of PEA, as is widely known in the literature, it is possible to use higher doses of PEA than those mentioned above, which were sufficient to obtain a synergistic effect on non-neuropathic inflammatory pain.

[0045] With respect to the amount of synergistic PEA with the NSAID, the additional PEA can also be in a form different from that used in combination with the NSAID, for example, if the PEA is in the form of um-PEA, the additional PEA can be either um-PEA, m-PEA, or non-micronized PEA, or vice versa.

[0046] Thus, the total daily dose of PEA administered to a subject, either in the form of a combination therapy or in the above compositions with an NSAID, can be 200-2000 mg / day, preferably 300-1500 mg / day or 400-1200 mg / day.

[0047] Such a daily dose can be divided into dosage units for administration, for example, 1 to 4 times daily. The dose also depends on the route selected for administration. It should be taken into account that dosage variations may be necessary depending on the age and weight of the patient and the degree of inflammatory pain being treated. The exact dose and route of administration are ultimately at the discretion of the attending physician.

[0048] For purposes of the present invention, the PEA alone, the NSAID alone, or a composition containing a PEA and an NSAID may be included in a pharmaceutical or veterinary preparation and may be formulated into a dosage form for oral, buccal, parenteral, rectal, topical, or transdermal administration.

[0049] For oral administration, the compounds of the present invention can be found in the form of hard or soft tablets or capsules, which are prepared in a conventional manner using, for example, pharmaceutically acceptable additives such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); excipients (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or inhibitors (e.g., sodium lauryl sulfate). Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can be, for example, in the form of liquids, syrups, or suspensions, or can be freeze-dried or granulated products that are reconstituted with water or other suitable vehicles before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoate, sorbic acid, benzoic acid, or salts thereof). The preparations can also conveniently contain flavoring agents, coloring agents, and sweeteners.

[0050] Preparations for oral administration may be suitably formulated to give controlled release of the active ingredient.

[0051] For buccal administration, the compounds of the invention may be in the form of tablets or granules formulated in conventional manner suitable for absorption at the level of the buccal mucosa. A typical buccal formulation is a tablet for sublingual administration.

[0052] The compound of the present invention can be formulated for parenteral administration by injection.Injection preparation can be provided as a single dose, for example, in a vial, with added preservative.Composition can be in the form of suspension, solution or emulsion in oily or aqueous vehicle, and can contain formulation substances such as suspending agent, stabilizer and / or dispersant.Alternatively, active ingredient or the mixture of active ingredients can be in the form of powder, which is reconstituted with suitable vehicle, for example, sterile water, before use.

[0053] The compounds of the present invention may be formulated according to rectal preparations such as suppositories or retention enemas, eg, containing common suppository base ingredients such as cocoa butter or other glycerides.

[0054] In addition to the above-mentioned preparations, the compound of the present invention can be formulated as depot preparation for administration for 1 day to 1 week.This long-acting preparation can be administered by implantation (for example, subcutaneous, transdermal or intramuscular) or intramuscular injection.Therefore, for example, composition can be formulated with suitable polymer or hydrophobic material (for example, in the form of emulsion in suitable oil) or ion exchange resin, or as a derivative that is minimally soluble.

[0055] The compounds or compositions of the present invention may be administered in the form of an oral or nasal spray.

[0056] The present invention further relates to a composition comprising or consisting of a mixture of palmitoylethanolamide, preferably ultra-micronized palmitoylethanolamide, a non-steroidal anti-inflammatory drug and a pharmaceutically acceptable excipient, wherein the PEA / NSAID weight ratio is 20:1 to 1:1, preferably 12:1 to 5:1, the PEA is contained in an amount of 200 to 2000 mg, and the NSAID is preferably selected from diclofenac, meloxicam, ibuprofen and ketoprofen.

[0057] In certain embodiments, the composition, or mixture of palmitoylethanolamides for separate or sequential administration, further comprises the PEA analog 2-pentadecyl-2-oxazoline (also referred to as PEA-OXA).

[0058] A further object of the present invention is 2-pentadecyl-2-oxazoline for use in the treatment of inflammatory pain, in particular non-neuropathic inflammatory pain, wherein the 2-pentadecyl-2-oxazoline is administered together or in combination with a non-steroidal anti-inflammatory drug, said administration being separate, joint or simultaneous, and preferably the non-steroidal anti-inflammatory drug is diclofenac.

[0059] The weight ratio of 2-pentadecyl-2-oxazoline to diclofenac is preferably 5:3 or more.

[0060] 2-pentadecyl-2-oxazoline is preferably administered at a dose of 100 mg to 1000 mg per day.

[0061] A further object of the present invention is a composition comprising or consisting of a mixture of 2-pentadecyl-2-oxazoline, a non-steroidal anti-inflammatory drug, preferably diclofenac, and pharmaceutically acceptable excipients, wherein 2-pentadecyl-2-oxazoline is preferably present in an amount of 100 mg to 1000 mg, and the weight ratio of 2-pentadecyl-2-oxazoline / diclofenac is preferably 5:3 or more.

[0062] The present invention further relates to dietary compositions, dietary supplements, complementary foods and foods for special medical purposes (FSMP) comprising PEA, preferably ultra-finely divided PEA.

[0063] The term "food for specific medical purposes" refers to a product approved in accordance with (EU) Regulation 2016 / 128. Such term refers to a product that is administered under medical supervision, and therefore such FSMP is assimilated to a drug.

[0064] The formulations according to the invention may be prepared according to conventional methods, for example as described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., NY, USA, 17th Edition, 1985 or Remington, The Science and Practice of Pharmacy, edited by Allen, Loyd V., Jr., 22nd Edition, 2012 or later editions. [Example]

[0065] Experimental Section (Miniaturization procedure) PEA was micronized as described above.

[0066] Ultra-micronization was carried out using a fluid jet system (specifically a Jetmill® model system) operating on compressed air jet "spiral technology".

[0067] Optimal refinement conditions: -Inner diameter of the micro-processing chamber: approx. 300 mm Fluid jet pressure 8 bar Product supply rate: 9~12kg / hour

[0068] (Determination of particle size distribution) Particle size distribution determination was performed on wet samples after 1 minute of sonication.

[0069] A Malvern Mastersizer 3000 instrument was used, operating on LALLS (Low Angle Laser Light Scattering) technology and the Fraunhofer calculation algorithm. The particle size distribution graph is shown in Figure 5.

[0070] (Biological Experiments) Experiment 1. Efficacy and synergism of PEA and NSAIDs in an animal model of CFA-induced inflammatory pain For in vivo experiments, male Sprague-Dawley rats (200–250 g) (Envigo, Varese, Italy) fed “ad libitum” and housed in cages with a controlled sleep / wake cycle were used.

[0071] Before the start of the study, animals were subjected to a one-week acclimatization period at the Center for Laboratory Animal Sheltering (Ce.SAL) of the University of Florence, following all experimental procedures and protocols that conformed to the principles of care and welfare of laboratory animals approved by the Italian Ministry of Health (Italian Legislative Decree 2014 / 26), the European Directive (EU Directive 2010 / 63) and the ARRIVE guidelines.

[0072] To induce inflammatory pain, 50 μL of complete Freund's adjuvant (CFA) was injected into the joint space between the tibiofibular and tarsal bones of the left leg after light anesthesia with 2% isoflurane. A control group underwent the same procedure and received an equal volume of saline (vehicle).

[0073] Animals were divided into 9 groups of 6 animals and treated acutely by oral administration in a single dose starting on day 7 after induction of joint damage. Group 1: Healthy rats given an intra-articular injection of saline (vehicle group) Group 2: Rats injected with CFA and treated with 1% CMC, corresponding to the vehicle in which the compounds were suspended for the treatment of the following groups (CFA group). Group 3: rats injected with CFA and treated with micronized PEA 10 mg / kg Group 4: CFA-injected rats treated with diclofenac 30 mg / kg Group 5: CFA-injected rats treated with diclofenac 3 mg / kg Group 6: Rats injected with CFA and treated with diclofenac 3 mg / kg + micronized PEA 10 mg / kg Group 7: CFA-injected rats treated with meloxicam 30 mg / kg Group 8: CFA-injected rats treated with meloxicam 3 mg / kg Group 9: Rats injected with CFA and treated with meloxicam 3 mg / kg + micronized PEA 10 mg / kg

[0074] The mean particle size of the micronized PEA (hereafter referred to as PEA for simplicity) used in the experiments was 0.2-10 μm, with a d90 of approximately 6 μm. All animals were subjected to paw pressure testing at the level of the ipsilateral paw, performed before (T0) or 15, 30, 45, and 60 min after a single administration of treatment (T15, T30, T45, and T60, respectively). Specifically, pain thresholds were calculated using an analgesimeter (Ugo Basile, Varese, Italy) by applying increasing pressure at a constant rate (32 g / s) with a blunt cone support to the dorsal surface of the ipsilateral paw relative to the injection of CFA (or vehicle). The nociceptive threshold was expressed as the force (decagram, dag) at which the animal responded by withdrawing its paw or vocalizing (Leighton GE et al. Kappa-opioid agonists produce antinociception after iv and icv but not intrathecal administration in the rat. Br J Pharmacol. 1988; 93: 553-60).

[0075] (statistical analysis) The values ​​obtained from the paw pressure test in the different treatment groups were compared with each other using a post-hoc analysis based on a generalized linear mixed model (GLMM) followed by a Tukey-Kramer correction for multiple comparisons, referring to a single treatment group and considering all time points. For synergy analysis, to verify whether the effect of combined administration of PEA and NSAID was greater than the sum of the individual effects of the two treatments used individually, the area under the curve (AUC) was considered and calculated with the trapezoidal rule for the following four treatment groups: CFA + vehicle CFA+PEA 10mg / kg CFA + NSAID 3mg / kg CFA+PEA(10mg / kg)+NSAID(3mg / kg)

[0076] AUC was analyzed by two-way analysis of variance (2 × 2 ANOVA) after plotting the mean values ​​according to the procedure described by Slinker BK. The statistics of synergism. J Mol Cell Cardiol. 1998 Apr;30(4):723-31. Values ​​were expressed as mean ± standard error of the mean (SEM). All statistical analyses were performed using the software SAS, version 9.4 (SAS Institute, Cary, NC, USA). A value of p < 0.05 was considered significant.

[0077] (Experimental results) For the diclofenac experiment, a comparison of the effects observed in each treatment group revealed the following (Figure 1): · Injection of CFA (dotted line with squares) induces significant inflammatory pain as indicated by a significant decrease in tolerance threshold (p<0.0001) versus the vehicle group (dotted line with diamonds). The group treated with 30 mg / kg diclofenac (solid line with diamonds) shows a significant increase in pain tolerance threshold compared to the CFA group (p=0.0004), whereas the groups treated with 3 mg / kg diclofenac (line with triangles) and PEA (line with filled circles) show no significant difference compared to the CFA group (p=1.0 and p=0.9674, respectively). Surprisingly, the combined use of PEA and low-dose diclofenac (3 mg / kg), which as noted above had no effect individually, significantly reduced pain (line with open circles; p=0.0047 for CFA).

[0078] It is noteworthy that the effect produced by the above combination was not significantly different from that obtained with 30 mg / kg diclofenac (p=0.9890), which means that by adding PEA to diclofenac, the same analgesic effect can be obtained even with a ten-fold reduction in the NSAID dose.

[0079] The synergy analysis performed on the AUC values ​​confirmed the synergistic effect between PEA and low-dose diclofenac. In particular, as plotted in Figure 2, the sum of the effects exerted by the individual compounds (small brackets) is smaller than the effect exerted by the combined use of the two (large brackets). Graphically, this is immediately apparent as the two segments are not parallel to each other.

[0080] The results of the ANOVA analysis are shown in Table 1, where the Pr>F corresponding to the line PEA*Dicl3 represents the probability that the superior effect shown by the two substances in combination over the sum of the effects of the individual substances is due to chance alone. As can be seen, this is a probability of less than 1 in 30, indicating a surprisingly significant synergistic effect between PEA and low-dose diclofenac. [Table 1]

[0081] Regarding the experiments with meloxicam, the results obtained are completely comparable to those observed above with diclofenac. Specifically, the following was found (Figure 3): · Injection of CFA (dotted line with squares) induces significant inflammatory pain as indicated by a significant decrease in tolerance threshold (p<0.0001) versus the vehicle group (dotted line with diamonds). Meloxicam administered at 30 mg / kg (line with diamonds) significantly counteracts the threshold decrease caused by CFA (p=0.0001), whereas meloxicam at 3 mg / kg (line with triangles) and PEA alone (line with filled circles) show no significant difference compared to the CFA group (p=0.1405 and p=0.9588, respectively). Surprisingly, the combined use of PEA and low-dose meloxicam (3 mg / kg), which as noted above had no effect individually, significantly reduced pain (line with open circles; p<0.0001 for CFA).

[0082] For meloxicam, as previously detected for diclofenac, the experiments showed that the effect produced by combining PEA with a low dose of meloxicam was not significantly different (p=1.0000) from the effect obtained with 30 mg / kg of meloxicam, meaning that by adding PEA to meloxicam, the same analgesic effect can be obtained even with a ten-fold reduction in the dose of the NSAID.

[0083] Synergy analysis performed on the AUC data confirmed the synergistic effect between PEA and low-dose meloxicam visually (Fig. 4) and based on the probabilities obtained from the Anova 2 × 2 analysis (Table 2). [Table 2]

[0084] Experiment 2: Efficacy and synergism of PEA and ibuprofen in an inflammatory pain model associated with rheumatoid arthritis (CIA, collagen-induced arthritis) Rheumatoid arthritis is a disease characterized by inflammatory pain, and involved joints exhibit swelling, stiffness, and often erosive processes. Female Lewis rats were maintained at constant temperature and humidity with a 12 / 12-hour light / dark cycle and allowed to acclimate for one week with free access to water and standard diet. Collagen induction of arthritis was performed as described by D et al. J Pharmacol Exp Ther 2011, 33:859-869. Briefly, chicken collagen type II (CII) was dissolved in 0.01 M acetic acid at a concentration of 2 mg / mL, while Mycobacterium tuberculosis H37Ra was added at a concentration of 2 mg / mL to prepare complete Freund's adjuvant (CFA). The immunization emulsion was prepared by emulsifying CII in an equal volume of CFA. Animals were immunized with this emulsion via intradermal injection at the base of the tail (day 0) and then boosted with a second injection on day 21. From days 25 to 35, animals were treated orally based on their assigned group as outlined below (N=6 rats / group): Sham (healthy, non-immunized and untreated control group) Vehicle (group with CIA treated with vehicle only) PEA (CIA group treated with micronized PEA at a dose of 30 mg / kg) IBU-ld (CIA group treated with low-dose ibuprofen, 5 mg / kg) IBU-hd (CIA group treated with high-dose ibuprofen, 30 mg / kg) PEA+IBU (CIA group treated with a combination of micronized PEA at a dose of 30 mg / kg and low-dose ibuprofen, 5 mg / kg)

[0085] Arthritis score, paw volume change (mL), and body weight change (g) were measured as indicators of inflammatory pain. The severity of arthritis was measured every other day starting on day 25 using the following score: 0 = no signs of arthritis, 1 = swelling and / or redness of the paw or toe, 2 = two joints affected, 3 = more than two joints affected, and 4 = severe arthritis of the entire paw and toe. The arthritis index for each subject was calculated by adding the four scores for each individual paw. Changes in paw volume compared to day 21 were assessed by paw plethysmography (Ugo Basile) every two days starting on day 25. Body weight changes were measured for each animal on day 21 and then every two days starting on day 25.

[0086] (statistical analysis) Selected inflammatory pain indices were analyzed using a generalized linear model (GLM) followed by post-hoc analysis based on Tukey-Kramer correction for multiple comparisons. To determine whether the combination of PEA and IBU exerted a synergistic effect (i.e., whether it produced an effect greater than the sum of the effects of the two treatments used individually), a factorial analysis of variance (ANOVA 2 × 2) was used according to the procedure described by Slinker BK (1998). Analytical results were expressed as mean ± standard error of the mean (SEM). All analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA). A P value of <0.05 was considered significant.

[0087] (Experimental results) After 6 days of treatment (i.e., starting on day 31), the first significant effects became apparent. More specifically, the scores recorded in the PEA+IBU group (10.0±0.58) and the IBUhd group (8.7±0.49) were significantly lower than those recorded in the untreated group (vehicle, 13.2±0.48; P=0.0017 and p<0.0001, respectively). The same observations were made at subsequent time points up to the end of the study (day 35), confirming that only the PEA+IBU combination and high-dose IBU were effective in reducing arthritis scores, whereas PEA alone and low-dose IBU were ineffective, as shown in FIG. 6.

[0088] At the end of treatment, it became clear that PEA and low-dose ibuprofen (IBUld) exerted a synergistic effect. As shown in the last column of the table obtained from a 2 × 2 factorial analysis of variance (Table 3), the probability that the effect of the combination was greater than the sum of the effects of the individual substances was actually less than 0.05 (p = 0.0018). Interestingly, the effect of PEA and low-dose ibuprofen was already synergistic at day 33 (p = 0.0052). [Table 3]

[0089] Quite similar results were obtained from paw volumetric analysis, with effects beginning to appear from day 6, with the combination of PEA+IBU (0.82±0.03 mL) and high-dose IBU (0.067±0.03 mL) significantly counteracting the volume increase compared to vehicle (1.06±0.04 mL; p<0.0001 for both comparisons). In contrast, single administration of PEA and IBU had no effect, as shown in Figure 7.

[0090] The results of a 2 × 2 factorial analysis showed that the synergistic effect of PEA and low-dose ibuprofen began not only at the end of treatment, but also on day 6. At these observation times, it was confirmed that the effect obtained by combining PEA and low-dose ibuprofen was indeed significantly higher than the sum of the effects of the individual treatments. The results of the analysis are shown in Table 4. [Table 4]

[0091] Similarly, pain-induced weight loss associated with the development of arthritis was significantly counteracted only by the combination and high dose of PEA+IBU, beginning on day 4 of treatment (corresponding to day 29 of the study) and continuing throughout the observation period (Figure 8). Neither PEA nor low-dose ibuprofen had any effect when administered individually.

[0092] As with the previous parameters, a 2x2 factorial analysis of variance for weight loss revealed a synergistic effect for the combination of the two substances (PEA and low-dose ibuprofen). The synergistic effect was particularly evident from the sixth day of treatment and was maintained at subsequent observations. The results of the analysis are shown in Table 5. [Table 5]

[0093] Experiment 3: Efficacy and synergistic effects of PEA and ibuprofen in the inflammatory pain model induced by plantar injection of carrageenan The experimental inflammatory pain model was induced by carrageenan (CAR) saline solution (0.1 mL of a 1% suspension of CAR in 0.85% saline). Experiments were performed in adult male Sprague-Dawley rats, with 6 animals in each of the following experimental groups: Group 1: Rats receiving CAR injections and treated with 1% CMC (corresponding to the vehicle in which the compounds were suspended for the treatments mentioned in the subsequent groups) (vehicle group) Group 2: Rats injected with CAR and treated with PEA 100 mg / kg Group 3: Rats injected with CAR and treated with ibuprofen 5 mg / kg Group 4: Rats injected with CAR and treated with PEA 100 mg / kg + ibuprofen 5 mg / kg Group 5: Rats injected with CAR and treated with ibuprofen 30 mg / kg

[0094] Animals were orally treated with a single dose 30 minutes before carrageenan injection. The PEA used in this experiment was in its raw (native) form. Pain was assessed using Von Frey filaments, and the mechanical tolerance threshold, i.e., the pressure (expressed in grams) tolerated before paw withdrawal, was recorded for each animal. Measurements were performed using an analgesimeter (Ugo Basile, Comerio, Varese, Italy) before the plantar injection of CAR and at the time of maximum injury (5 hours later).

[0095] (statistical analysis) The effects on pain were analyzed using a generalized linear model (GLM) followed by post-hoc analysis based on Tukey-Kramer correction for multiple comparisons. To determine whether the combination of PEA and IBU exerted a synergistic effect (i.e., whether it produced an effect greater than the sum of the effects of the two treatments used individually), a factorial analysis of variance (ANOVA 2 × 2) was used according to the procedure described by Slinker BK (1998). Analytical results were expressed as mean ± standard error of the mean (SEM). All analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA). A P value of <0.05 was considered significant.

[0096] (Experimental results) As shown in Figure 9, co-treatment with PEA and low-dose ibuprofen (but not mono-treatment) significantly increased the tolerance threshold compared to the vehicle-treated group (p=0.0048). Surprisingly, this effect was comparable to that of high-dose ibuprofen (p=0.9897), indicating that the addition of an inactive dose of PEA resulted in significant analgesic effects at a similarly inactive dose of ibuprofen (5 mg / kg), one-sixth the dose shown to be active (30 mg / kg).

[0097] A 2 × 2 ANOVA factorial analysis also revealed that PEA and low-dose ibuprofen had a synergistic effect on pain, confirmed by the effect of the combination being significantly greater than the sum of the effects of the individual substances (p<0.05; Table 6). [Table 6]

[0098] Experiment 4. Efficacy and synergism of chronic administration of PEA or PEA-OXA and diclofenac in an animal model of CFA-induced inflammatory pain The inflammatory pain model was induced by injecting complete Freund's adjuvant (CFA, Sigma-Aldrich) into the tibiotarsal joint of male Sprague-Dawley rats (Charles River) housed in 26 × 41 cm cages at the Animal Husbandry Center. Experimental animals at the University of Florence (Ce.SAL) had a 12-hour circadian cycle, water and food (standard chow) were available ad libitum, and the temperature was 23 ± 1°C. Intra-articular injections were performed after light anesthesia with 2% isoflurane according to the method described by Butler et al. (Pain 48:73-81, 1992). The skin surrounding the injection site was sterilized with 75% ethyl alcohol. A 28-gauge needle was then inserted into the joint cavity, and 50 μL of CFA was injected. The animals were then divided into the following treatment groups (N = 8): Sham (control, injected into the tibiotarsal joint with the same volume of physiological solution as used in CFA animals) Vehicle (CMC 1%) Diclofenac (3 mg / kg) Diclofenac (30 mg / kg) PEA (10 mg / kg) PEA-OXA (10 mg / kg) PEA (5 mg / kg) + diclofenac (3 mg / kg) PEA (10 mg / kg) + diclofenac (3 mg / kg) PEA (10 mg / kg) + diclofenac (30 mg / kg) PEA-OXA (5 mg / kg) + diclofenac (3 mg / kg)

[0099] The test molecules, used individually and in combination, were suspended in 1% CMC and administered orally daily from days 1 to 14 (chronic treatment). The mean particle size of the PEA used in these experiments was 0.2–10 μm, with a d90 of approximately 6 μm. To clarify the effect of repeated treatment on joint pain, behavioral tests were performed 24 h after the last administration. Inflammatory pain induced by CFA injection was measured using the paw pressure test. Briefly, before and 60 min after CFA injection, pressure increasing at a constant rate (32 g / s) was applied to the ipsilateral paw of the rat using a blunt cone support. The nociceptive threshold was expressed as the force at which the animal responded by paw withdrawal or vocalization (Leighton et al., Br J Pharmacol 93:553–560, 1988). For this purpose, an analgesiometer (Ugo Basile, Varese) capable of quantifying mechanical hyperalgesia was used. Additionally, spontaneous pain was assessed using an incapacitance test, which assesses fluctuations in postural balance with an "incapacitance" device (Linton Instrumentation, UK), a scale that measures the force exerted by each foot simultaneously but separately (Fernandes et al., Arthritis Res Ther. 2016 Jan 11;18:7).

[0100] Briefly, rats were trained to stand on their hind legs in a box with an inclined surface (65 degrees to the horizontal) placed on an "incapacity" apparatus. In the absence of hind paw injury, rats exert equal force on both hind paws, indicating postural balance; conversely, unequal weight distribution indicates a unilaterally decreased pain threshold. Each animal's value represents the average result of three consecutive measurements. Data are expressed in grams as the difference between the weight applied to the paw contralateral to the lesion and the weight applied to the paw ipsilateral to the lesion (Δweight). Results were expressed in terms of "pain efficacy," defined as the percentage inhibition of inflammatory pain induced by CFA (mean ± SEM) and calculated according to the formula: 100 × (treatment - VEIC) / (CTRL - VEIC).

[0101] (statistical analysis) The effects on pain were analyzed using a generalized linear model (GLM) followed by post-hoc analysis based on Tukey-Kramer correction for multiple comparisons. The results were expressed as mean ± standard error of the mean (SEM). To determine whether the molecules exerted a synergistic effect, we analyzed whether the degree of inhibition of inflammatory pain by CFA was greater when the two substances were combined compared to when each substance was used individually. For this purpose, we used a factorial analysis of variance (ANOVA 2 × 2) according to Slinker BK (1998). All analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA). A P value of <0.05 was considered significant.

[0102] (Experimental results) Daily monitoring of the animals revealed significant toxicity associated with long-term treatment with diclofenac at a dose of 30 mg / kg; due to the high mortality rate, it was not possible to consider this treatment group for further analysis. Figure 10 shows the nociceptive threshold (decagrams) measured by paw pressure testing 14 days after treatment. As can be seen, adding PEA or PEA-OXA to diclofenac provides a therapeutic benefit, as indicated by a significant increase in the nociceptive threshold in the co-treated group compared with the group treated with diclofenac alone. Furthermore, it can be seen that the combination of PEA (10 mg / kg) and diclofenac (3 mg / kg) can completely reverse the painful effects of CFA.

[0103] A 2 × 2 ANOVA factorial analysis revealed that PEA exerted a synergistic effect compared with diclofenac (3 mg / kg) in controlling spontaneous pain, confirmed by the fact that combining PEA with diclofenac (5 mg / kg or 10 mg / kg) produced pain relief greater than the sum of the analgesic effects obtained with the individual substances (p = 0.014 for the combination with PEA 10 mg / kg, p < 0.0001 for the combination with PEA 5 mg / kg; Tables 7 and 8). [Table 7] [Table 8]

[0104] It is important to emphasize that the synergy test was performed by comparing the PEA5 and Dicl3 co-treated group with the group treated individually with Dicl3 mg / kg and PEA 10 mg / kg in the absence of the group treated individually with PEA 5 mg / kg, a double dose of PEA compared to the group treated with the PEA-NSAID combination, and surprisingly, the analysis confirmed a statistically significant superiority of the analgesic effect of this combination.

[0105] Similar observations were made when determining whether PEA-OXA exerted a synergistic effect with diclofenac. Again, a group co-treated with PEA-OXA (5 mg / kg) and diclofenac (3 mg / kg) (and a group treated with diclofenac alone at the same dose) was compared with a group treated with twice the dose of PEA-OXA. Surprisingly, however, a 2 × 2 ANOVA analysis showed that the effect of the combination in reducing mechanical hyperalgesia was synergistic rather than additive, i.e., significantly greater than the sum of the effects of the single treatments (p = 0.003, Table 9). [Table 9]

[0106] In view of the above results, inflammatory pain that can be treated according to the present invention preferably comprises: · Pain caused by tissue damage; ·Postoperative pain; ·toothache; · Pain and inflammation of the mouth and throat; · Muscle and rheumatic pain; · Menstrual pain (dysmenorrhea); · Inflammatory pain associated with pouchitis and bursitis; Inflammatory pain associated with tendonitis and tenosynovitis; · Inflammatory pain associated with osteoarthritis; Inflammatory pain associated with periarthritis; Inflammatory pain associated with rheumatoid arthritis; Inflammatory pain associated with ankylosing spondylitis; Inflammatory pain associated with acute gout is selected from.

[0107] The present invention is further illustrated by the following formulation examples.

[0108] (Formulation example) um-PEA = Ultrafine Palmitoylethanolamide m-PEA = micronized palmitoylethanolamide non-m PEA = non-micronized palmitoylethanolamide PEA-OXA = 2-pentadecyl-2-oxazoline

[0109] [Table 10]

[0110] [Table 11]

[0111] [Table 12]

[0112] [Table 13]

[0113] [Table 14]

[0114] [Table 15]

[0115] [Table 16]

[0116] [Table 17]

[0117] [Table 18]

[0118] [Table 19]

[0119] Table 20

[0120] Table 21

[0121] Table 22

[0122] Table 23

[0123] Table 24

[0124] Table 25

[0125] Table 26

[0126] Table 27

[0127] Table 28

[0128] Table 29

[0129] Table 30

[0130] Table 31

[0131] Table 32

Claims

1. 1. Palmitoylethanolamide for use in the treatment of inflammatory pain, particularly non-neuropathic inflammatory pain, wherein the palmitoylethanolamide is optionally administered together or in combination with a non-steroidal anti-inflammatory drug, said administration being separate, combined or simultaneous.

2. 2. Palmitoylethanolamide for use according to claim 1, wherein the palmitoylethanolamide is in non-micronized form having a particle size distribution, defined as a volume percentage and measured by laser light scattering, represented by a distribution curve having a mode above 10 μm, preferably above 20 μm.

3. 2. Palmitoylethanolamide for use according to claim 1, wherein the palmitoylethanolamide is in micronized form having a particle size distribution, defined as a volume percentage, measured by laser light scattering and represented by a distribution curve having a mode between 6 μm and 10 μm.

4. 2. The palmitoylethanolamide for use according to claim 1, wherein the palmitoylethanolamide is in ultra-micronized form having a particle size distribution, defined as a volume percentage, measured by laser light scattering and represented by a distribution curve having a mode below 6 μm and above 0.5 μm.

5. 5. Palmitoylethanolamide for use according to claim 4, having a particle size distribution, defined as a volume percentage, measured by laser light scattering and measured on a Malvern Mastersizer 3000 instrument using the Fraunhofer calculation algorithm, in which at least 90% by volume, preferably at least 95% by volume, of the particles have a particle size of less than 6 μm.

6. 5. Palmitoylethanolamide for use according to claim 4, wherein the palmitoylethanolamide has a particle size distribution, defined as a volume percentage, measured by laser light scattering, measured on a Malvern Mastersizer 3000 instrument using the Fraunhofer calculation algorithm, and having a mode of 2-4 μm, with 100% by volume of the particles being less than 10 μm and at least 60% by volume of the particles being less than 3 μm.

7. Palmitoylethanolamide for use according to any one of claims 1 to 6, wherein the PEA and NSAID are administered in a PEA / NSAID weight ratio of 20:1 to 1:1, preferably 12:1 to 5:

1.

8. 8. Palmitoylethanolamide for use according to claim 7, wherein the PEA / NSAID weight ratio is from 11:1 to 3:1, more preferably from 10:1 to 5:1, if the PEA is in ultra-micronized form, and the PEA / NSAID weight ratio is preferably from 20:1 to 5:1, more preferably from 18:1 to 10:1, if the PEA is in micronized or non-micronized form.

9. 9. Palmitoylethanolamide for use according to any one of claims 1 to 8, wherein the total daily dose of PEA administered to the subject is 200 to 2000 mg / day, preferably 300 to 1500 mg / day, or 400 to 1200 mg / day.

10. 10. Palmitoylethanolamide for use according to any one of claims 1 to 9, wherein the palmitoylethanolamide and the NSAID are comprised in a pharmaceutical or veterinary formulation and are formulated into a dosage form for oral, buccal, parenteral, rectal, topical or transdermal administration.

11. 10. Palmitoylethanolamide for use according to any one of claims 1 to 9, wherein the palmitoylethanolamide is comprised in a dietary composition, a dietary supplement, a complementary food or a food for special medical purposes (FSMP).

12. 12. Palmitoylethanolamide for use according to any one of claims 1 to 11, wherein the NSAID is selected from salicylates, such as acetylsalicylic acid; acetic acid derivatives such as indomethacin, diclofenac, ketorolac, aceclofenac; propionic acid derivatives, such as ibuprofen, ketoprofen and naproxen; oxicam derivatives, such as piroxicam and meloxicam; fenamates, such as mefenamic acid; coxibs or COX-2 inhibitors, such as cerocoxib, etoricoxib and parecoxib; nimesulide; norniflumate / niflumic acid.

13. Palmitoylethanolamide for use according to any one of claims 1 to 12, further comprising the administration of 2-pentadecyl-2-oxazoline.

14. Non-neuropathic inflammatory pain - pain caused by tissue injury; ・Postoperative pain; ·toothache; - Pain and inflammation of the mouth and throat; -muscular and rheumatic pain; - Menstrual pain (dysmenorrhea); - Inflammatory pain associated with pouchitis and bursitis; - Inflammatory pain associated with tendonitis and tenosynovitis; - inflammatory pain associated with osteoarthritis; - Inflammatory pain associated with periarthritis; - inflammatory pain associated with rheumatoid arthritis; - Inflammatory pain associated with ankylosing spondylitis; - Inflammatory pain associated with acute gout Palmitoylethanolamide for use according to any one of claims 1 to 13, wherein the pain is selected from the group consisting of:

15. 1. A composition comprising or consisting of a mixture of palmitoylethanolamide, preferably ultra-micronized palmitoylethanolamide, a non-steroidal anti-inflammatory drug, a pharmaceutically acceptable excipient, and optionally 2-pentadecyl-2-oxazoline, wherein the PEA / NSAID weight ratio is from 20:1 to 1:1, preferably from 12:1 to 5:1, the PEA is present in an amount of from 200 to 2000 mg, and the NSAID is preferably selected from diclofenac, meloxicam, ibuprofen, and ketoprofen.

16. 2-pentadecyl-2-oxazoline for use in the treatment of inflammatory pain, particularly non-neuropathic inflammatory pain, wherein the 2-pentadecyl-2-oxazoline is administered together or in combination with a non-steroidal anti-inflammatory drug, said administration being separate, joint or simultaneous.

17. 2-pentadecyl-2-oxazoline for use according to claim 16, wherein the non-steroidal anti-inflammatory drug is diclofenac.

18. 2-pentadecyl-2-oxazoline for use according to claim 17, wherein the weight ratio of 2-pentadecyl-2-oxazoline / diclofenac is 5:3 or more.

19. 2-pentadecyl-2-oxazoline for use according to any one of claims 16 to 18, wherein the 2-pentadecyl-2-oxazoline is administered in a dose of 100 mg to 1000 mg per day.

20. A composition comprising or consisting of a mixture of 2-pentadecyl-2-oxazoline, a non-steroidal anti-inflammatory drug, preferably diclofenac, and a pharmaceutically acceptable excipient, wherein the 2-pentadecyl-2-oxazoline is preferably contained in an amount of 100 mg to 1000 mg, and the weight ratio of 2-pentadecyl-2-oxazoline to diclofenac is preferably 5:3 or more.

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